9-97675161-A-G

Variant names:

• chr9-97675161-A-G
• rs3176753
• NM_000380.4:c.*278T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000380.4(XPA):​c.*278T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 582,410 control chromosomes in the GnomAD database, including 584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (446 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (138 hom.)
• Consequence: XPA NM_000380.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.42
• Publications: 4 publications found

Genes affected

XPA (HGNC:12814): (XPA, DNA damage recognition and repair factor) This gene encodes a zinc finger protein plays a central role in nucleotide excision repair (NER), a specialized type of DNA repair. NER is responsible for repair of UV radiation-induced photoproducts and DNA adducts induced by chemical carcinogens and chemotherapeutic drugs. The encoded protein interacts with DNA and several NER proteins, acting as a scaffold to assemble the NER incision complex at sites of DNA damage. Mutations in this gene cause Xeroderma pigmentosum complementation group A (XP-A), an autosomal recessive skin disorder featuring hypersensitivity to sunlight and increased risk for skin cancer. [provided by RefSeq, Aug 2017]

XPA Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-97675161-A-G is Benign according to our data. Variant chr9-97675161-A-G is described in ClinVar as Benign. ClinVar VariationId is 364082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000380.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	NM_000380.4	MANE Select	c.*278T>C		3_prime_UTR	Exon 6 of 6	NP_000371.1	P23025
	XPA	NM_001354975.2		c.*278T>C		3_prime_UTR	Exon 6 of 6	NP_001341904.1
	XPA	NR_027302.2		n.1379T>C		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.*278T>C		3_prime_UTR	Exon 6 of 6	ENSP00000364270.5	P23025
	XPA	ENST00000905836.1		c.*278T>C		3_prime_UTR	Exon 3 of 3	ENSP00000575895.1
	XPA	ENST00000462523.5	TSL:5	n.*536T>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000433006.1	F2Z2T2

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6200 AN: 152102 Hom.: 446 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.00850 AC: 1112 AN: 130754 AF XY: 0.00684

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00632

Gnomad ASJ exome AF: 0.00272

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000461

Gnomad OTH exome AF: 0.00500

GnomAD4 exome AF: 0.00607 AC: 2613 AN: 430190 Hom.: 138 Cov.: 3 AF XY: 0.00460 AC XY: 1080 AN XY: 234684

African (AFR) AF: 0.140 AC: 1934 AN: 13806

American (AMR) AF: 0.00765 AC: 238 AN: 31128

Ashkenazi Jewish (ASJ) AF: 0.00373 AC: 64 AN: 17148

East Asian (EAS) AF: 0.00 AC: 0 AN: 22994

South Asian (SAS) AF: 0.000444 AC: 27 AN: 60852

European-Finnish (FIN) AF: 0.0000602 AC: 1 AN: 16602

Middle Eastern (MID) AF: 0.00585 AC: 11 AN: 1880

European-Non Finnish (NFE) AF: 0.000314 AC: 76 AN: 242020

Other (OTH) AF: 0.0110 AC: 262 AN: 23760

GnomAD4 genome AF: 0.0408 AC: 6206 AN: 152220 Hom.: 446 Cov.: 32 AF XY: 0.0394 AC XY: 2932 AN XY: 74432

African (AFR) AF: 0.141 AC: 5859 AN: 41504

American (AMR) AF: 0.0162 AC: 247 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68024

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0153 Hom.: 196

Bravo AF: 0.0464

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Xeroderma pigmentosum group A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.58
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3176753; hg19: chr9-100437443;